It is now currently well recognized from clinical studies that b-adrenergic receptor (bAR) blockade therapy is useful in treating clinical heart failure (HF). Despite the preponderance of clinical data favoring the use of bAR blockade in the treatment of HF, little is known regarding the cellular and molecular mechanisms underlying the salutary action of this therapy. The overall goal of this project is to explore these mechanisms. To accomplish this goal we will investigate distal bAR signaling in terms of stress-activated kinases following up the provocative leads developed related to these proteins in mediating the cardiomyopathy in overexpressed Gsa mice and their inhibition by bAR blockade. A second approach is to follow the logic that potentially similar transcriptional and signaling mechanisms mediating cardiomyopathy are not only exhibited in overexpressed Gsa mice but also in b1-AR, b2-AR and protein kinase A (PKA) overexpressed mice and conversely, and that alleviation of the cardiomyopathy in these four models by treatment with bAR blockade will also involve common underlying mechanisms. There are 3 major hypotheses: Hypothesis A: The beneficial action of bAR blockade in HF involves inhibition of stress-activated kinase pathways, both in terms of activity and protein levels. Hypothesis B: Since overexpression of Gsa, b1- b2-AR, PKA and all lead to cardiomyopathy, our hypothesis is that by examining their common genomic patterns during the development of the cardiomyopathy and after bAR blockade, key insight will be provided into mechanisms common to the four models, which relate to the role of sympathetic nervous system activation in the development of HF and to the mechanism of bAR blockade therapy. Hypothesis C: Breakthroughs in HF research will be derived from identifying novel, unexpected changes in gene and protein expression induced by disease states. We therefore propose that the development of cardiomyopathy in the overexpressed Gsa, b1-, b2-AR, and PKA mice will be characterized by expression of novel genes or proteins, i.e., those genes or proteins not previously thought to have a role in cardiac regulation, and unexpected modifications of proteins.